Human pericytes degrade diverse alpha-synuclein aggregates

Parkinson's disease (PD) is a progressive, neurodegenerative disorder characterised by the abnormal accumulation of alpha-synuclein (alpha-syn) aggregates. Central to disease progression is the gradual spread of pathological alpha-syn. alpha-syn aggregation is closely linked to progressive neuron loss. As such, clearance of alpha-syn aggregates may slow the progression of PD and lead to less severe symptoms. Evidence is increasing that non-neuronal cells play a role in PD and other synucleinopathies such as Lewy body dementia and multiple system atrophy. Our previous work has shown that pericytes-vascular mural cells that regulate the blood-brain barrier-contain alpha-syn aggregates in human PD brains. Here, we demonstrate that pericytes efficiently internalise fibrillar alpha-syn irrespective of being in a monoculture or mixed neuronal cell culture. Pericytes cleave fibrillar alpha-syn aggregates (Fibrils, Ribbons, fibrils65, fibrils91 and fibrils110), with cleaved alpha-syn remaining present for up to 21 days. The number of alpha-syn aggregates/cell and average aggregate size depends on the type of strain, but differences disappear within 5 five hours of treatment. Our results highlight the role brain vasculature may play in reducing alpha-syn aggregate burden in PD.